The present invention relates to new beta-keto esters which are useful as precursors for compounds, especially organoleptic compounds, such as flavours, fragrances and masking agents and antimicrobial compounds and insect repellents.
A principal strategy currently employed in imparting odours to consumer products is the admixing of the fragrance directly into the product. There are, however, several drawbacks to this strategy. The fragrance material can be too volatile and or too soluble, resulting in fragrance loss during manufacturing, storage, and use. Many fragrance materials are also unstable over time. This again results in loss during storage.
In many consumer products it is desirable for the fragrance to be released slowly over time. Micro-encapsulation and inclusion complexes with cyclodextrins have been used to help decrease volatility, improve stability and provide slow-release properties. However, these methods are for a number of reasons often not successful. In addition, cyclodextrins can be too expensive.
Fragrance precursors for scenting fabrics being washed in the presence of a lipase-containing detergents are described in WO 95/04809. The fragrance precursors contained in the detergent and/or in the softener are cleaved by the lipase and a single odoriferous compound, either an odoriferous alcohol or aldehyde or ketone is yielded. Thereby a prolonged scenting effect on the fabric is obtained.
Beta-amino ester compounds of perfume alcohols and their use as precursors for active alcohols which are released under alkaline conditions are described in the EP-A 0 771 786.
Certain beta-ketoester pro-accords for personal care and personal hygiene articles are disclosed in WO 98/07407.
The present invention provides beta-keto ester compounds which are useful as precursors for organoleptic compounds, especially for flavours, fragrances and masking agents and antimicrobial compounds.
One object of the present invention is to provide new precursors for compounds with different activities. A further object of the invention is to provide new compounds which are stable under transport and storage conditions. A further object of the present invention is to provide precursor molecules supplying different active compounds simultaneously or successively.
The present invention relates to new beta-keto esters of the formula I 
wherein
Y is the residue of an organoleptic ketone or lactone of the formula YH, and if Y is the residue of a cyclic ketone, the carbonyl group may be part of the cyclic structure.
R is H or the residue of a phenol or of a mono- or polyalcohol of the formula Rxe2x80x94(OH)s with sxe2x89xa71,
p=1, 2
nxe2x89xa71 and
q=1,2
whereby if n greater than 1 the rests Y may be different or the same with the exception of
3-oxo-5-(2,6,6-trimethyl-cyclohex-1-enyl)-pentanoic acid methyl ester,
3-oxo-5-(2,6,6-trimethyl-cyclohex-2-enyl)-pentanoic acid methyl ester,
3-oxo-5-(2,6,6-trimethyl-cyclohex-1-enyl)-pent-4-enoic acid methyl ester,
3-oxo-2-(2,6,6-trimethyl-cyclohex-1-enylmethyl)-butyric acid ethyl ester,
3-isopropyl-6-methyl-2-oxo-cyclohexane carboxylic acid methyl ester, and
3-isopropyl-6-methyl-2-oxo-cyclohexane carboxylic acid ethyl ester.
The compounds of formula I are not limited to any particular stereoisomers. All possible stereoisomers (E/Z isomers, enantiomers, diastereomers) and all mixtures are thus included within the scope of the invention.
The compounds of formula I are mostly or nearly odourless at room temperature, atmospheric conditions and about 20 to 100% relative humidity. However, under activating conditions, they are cleaved and one or more active compounds with organoleptic and/or antimicrobial properties are generated.
The activating conditions which lead to cleavage and the desired active compounds comprise the presence of skin bacteria, especially axilla bacteria, of an enzyme such as protease or lipase, elevated temperature, acidic or alkaline pH-values or light. Under activating conditions the beta-keto esters of formula I are cleaved into an unstable beta-keto acid and an alcohol or phenol or water (if Rxe2x95x90H), then the beta-keto acid decomposes to a ketone or lactone which may be organoleptic according to the following: 
(thereby ROH is an alcohol or phenol which may be organoleptic) 
The compounds of formula I, upon cleavage, provide ketones or lactones and/or alcohols or phenols optionally having organoleptic and/or antimicrobial activity and therefore permit the development of useful consumer products with enhanced organoleptic and/or antimicrobial properties. The organoleptic compounds obtained are useful as fragrances, flavours and masking agents and antimicrobial agents. Therefore, the invention also relates to the use of all compounds of formula I as precursors for organoleptic compounds, e.g. flavours, fragrances, masking agents and as precursors for antimicrobial agents.
The beta-keto esters of formula I can act as fragrance precursors in personal care products, in laundry products, cleaning compositions, pet care products and environment scents such as air fresheners. They can also act as precursors for odour masking agents in the same products as the fragrance precursors. They also can act as precursors for antimicrobial agents. Further, they can act as flavour precursors in food and beverage products. The fragrance precursors and the precursors for odour masking agents as well as the flavour precursors of the invention may be used individually in an amount effective to enhance or to mask the characteristic odour or flavour of a material. More commonly, however, the compounds are mixed with other fragrance or flavour components in an amount sufficient to provide the desired odour or flavour characteristics.
Due to the in situ generation of the active compounds the desired effect is prolonged and the substantivity on different substrates is enhanced. If two or more active compounds are provided, they can be generated, depending on the precursor and/or the activating conditions, simultaneously or successively. Further, the precursors of the invention provide slow release of the active compounds.
Compounds of formula I wherein Y is the residue of an organoleptic ketone or lactone are preferred.
Compounds of formula I wherein Rxe2x95x90H or the residue of a nonfragrant phenol or of a nonfragrant mono- or polyalcohol, especially having more than 3-C atoms are also preferred.
One preferred group of beta-keto esters of formula I are those in which Y is the residue of a cyclic ketone where the carbonyl group is part of the cyclic structure.
Another preferred group of beta-keto esters of formula I are those in which
Y is a residue of the formula 
wherein R1 is an aliphatic rest optionally substituted by one or more cycloaliphatic or aromatic rests or R1 is an cycloaliphatic rest optionally substituted by one or more aliphatic rests,
R2 is H or an aliphatic rest.
R3 is H or an aliphatic rest and
R1, R2 and R3 may be the same or different,
x=0 or 1 and
when x=1, R1 and R2 together may form an aliphatic ring.
Compounds of formula I may generate the following organoleptic ketones of formula YH:
2-heptyl-cyclopentanone
2,2,6,10-tetramethyltricyclo[5.4.0.0(6, 10)]-undecan-4-one benzylacetone*
1,2,3,5,6,7-hexahydro-1,1,2,3,3-pentamethyl-4H-inden-4-one*
2,5-dimethyl-oct-2-en-6-one**
2-(butan-2-yl)-cyclohexanone*
2-hexyl-cyclopent-2-en-1-one*
2-(1-methylethyl)-5-methyl-cyclohexanone*
2-(2-methylethyl)-5-methyl-cyclohexanone**
3-methyl-cyclopentadecanone
4-(1,1-dimethylpropyl)pentyl-cyclohexanone*
3-oxo-2-pentyl-cyclopentane-acetic acid methyl ester**
1-(1,2,3,4,5,6,7,8,-octahydro-2,3,8,8-tetramethyl-2-naphthalenyl)-ethanone*
3-methyl-5-propyl-cyclohex-2-en-1-one*
4-(2,6,6-trimethylcyclohex-1-en-1yl)butan-2-one**
4-(2,6,6-trimethylcyclohex-2-en-1-yl)butan-2-one**
2-methyl-5-(1-methylethenyl)-cyclohex-2-en-1-one*
cyclopentadecanone**
1-(4-hydroxyphenyl)-butan-3-one**
4-benzo-1,3-dioxo-5-yl-but-2-one**
4-(1,3-benzodioxol-5-yl)-2-butanone**
nonan-3-one*
nonan-2-one*
octan-2-one*
2-heptanone*
butan-2-one*
6-methyl-hept-5-en-2-one*
6,10-dimethyl-undeca-5,9-dien-2-one*
1-(2,4,4-trimethyl-2-cyclohexen-1-yl)-2-buten-1-one*
carvone**
2-pentyl-cyclopent-2-en-1-one
3-methyl-2-pentyl-cyclopent-2-en-1-one**
2-hexylidenecyclopentanone*
3,5-diethyl-5,6-dimethyl-2-cyclohexenone*
4,4A,5,6,7,8-hexahydro-6-isopropenyl-4,4A-dimethyl-2(3H)-naphthalenone**
3-methyl-6-propylidenecyclohexanone*
4-(1-methylethyl)cyclohex-2-en-1-one
(E)-oct-3-en-2-one
1-(2,3,4,7,8,8A-hexahydro-3,6,8,8-tetramethyl-1H-3A,7-methanoazulen-5-yl)ethanone*
2-hydroxy-3,5-dimethyl-cyclopent-2-en-1-one*
1-(3,3-dimethyl-1-cyclohexen-1-yl)ethanone*
1-(2,4,6-trimethylcyclohex-3-en-1-yl)but-1-en-3-one
acetylisolongifolene
2-(3-methylbut-2-en-1-yl)-3-methyl-cyclopent-2-en-1-one
3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-3-en-2-one*
5-butylidene-2,2,4-trimethylcyclopentanone
4,4A,5,6,7,8-hexahydro-6-isopropyl-2(3H)-naphthalenone
4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-butan-2-one**
4-methoxyphenylethanone**
acetophenone*
1-(2-naphthalenyl)-ethanone**
3-methyl-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-one**
2-acetylpyrazine*
3,5,5-trimethyl-cyclohex-2-en-1,4-dione*
(E)-5-methyl-2-hepten-4-one
dec-3-en-2-one
2-ethyl-3,6,6-trimethylcyclohex-2-enyl-but-2-en-1-one
2,4,4,5,5-pentamethyl-1-cyclopenten-1-yl-ethanone*
whereby * indicates the preferred ketones and ** indicate the more preferred ketones.
Compounds of formula I may generate the following lactones of formula HY
6-methyl-pyran-2-one
5-heptyl-dihydro-furan-2-one*
5-pentyldihydro-2(3H)-furanone*
5-(3-hexenyl)dihydro-5-methyl-(Z)-2(3H)-furanone
5-hexyldihydro-5-methyl-2(3H)-furanone
5-hexyldihydro-2(3H)-furanone*
5-octyldihydro-2(3H)-furanone
8-(1-methylethyl)-1-oxaspiro[4.5]-decan-2-one*
8-methyl-1-oxaspiro[4.5]-decan-2-one
8-ethyl-1-oxaspiro[4.5]-decan-2-one
5-(1,5-dimethyl-4-hexanyl)dihydro-2(3H)-furanone
2-oxo-5-butyl-tetrahydrofuran*
4-methyl-5-pentyl-dihydro-2(3H)-furan-2-one
5-hexyldihydro-5-methyl-2(3H)-furanone
dihydro-5-methyl-5-vinyl-2(3H)-furanone
octahydro-2H-1-benzopyran-2-one
tetrahydro-6-pentyl-2H-pyran-2-one
tetrahydro-6-hexyl-2H-pyran-2-one
tetrahydro-6-heptyl-2H-pyran-2-one
tetrahydro-6-(3-pentenyl)-(E)-2H-pyran-2-one
tetrahydro-6-(2-pentenyl)-(Z)-2H-pyran-2-one
(E)-oxacycloheptadec-10-en-one**
oxacyclohexadecan-2-one**
dodeca-12-olide
where by * indicates the preferred lactones and ** indicate the more preferred lactones.
Examples of organoleptic monoalcohols and phenols constituting the residue R- in the compounds of formula I and generated upon cleavage are:
amyl alcohol
hexyl alcohol*
2-hexyl alcohol*
heptyl alcohol*
octyl alcohol*
nonyl alcohol*
decyl alcohol*
undecyl alcohol*
lauryl alcohol*
myristic alcohol
3-methyl-but-2-en-1-ol*
3-methyl-1-pentanol
cis-3-hexenol*
cis-4-hexenol*
3,5,5-trimethyl hexanol
3,4,5,6,6-pentamethylheptan-2-ol*
citronellol*
geraniol*
oct-1-en-3-ol
2,5,7-trimethyl octan-3-ol
2-cis-3,7-dimethyl-2,6-octadien-1-ol
6-ethyl-3-methyl-5-octen-1-ol*
3,7-dimethyl-oct-3,6-dienol*
3,7-dimethyloctanol*
7-methoxy-3,7-dimethyl-octan-2-ol *
cis-6-nonenol*
5-ethyl-2-nonanol
6,8-dimethyl-2-nonanol*
2,2,8-trimethyl-7(8)-nonene-3-ol
nona-2,6-dien-1-ol
4-methyl-3-decen-5-ol*
dec-9-en-1-ol
benzylalcohol
2-methyl undecanol
10-undecen-1-ol
1-phenyl ethanol*
2-phenyl ethanol*
2-methyl-3-phenyl-3-propenol
2-phenyl propanol*
3-phenyl propanol*
4-phenyl-2-butanol
2-methyl-5-phenyl pentanol*
2-methyl-4-phenyl-pentanol*
3-methyl-5-phenyl-pentanol*
2-(2-methylphenyl)-ethanol*
4-(1-methylethyl)benzene methanol
4-(4-hydroxyphenyl)butan-2-one*
2-phenoxy ethanol*
4-(1-methylethyl)-2-hydroxy-1-methyl benzene
2-methoxy-4-methyl phenol
4-methyl phenol
anisic alcohol*
p-tolyl alcohol*
cinnamic alcohol*
vanillin*
ethyl vanillin*
eugenol*
isoeugenol*
thymol
anethol*
decahydro 2-naphthalenol
borneol*
cedrenol*
farnesol*
fenchyl alcohol*
menthol*
3,7,11-trimethyl-2,6,10-dodecatrien-1-ol
alpha ionol*
tetrahydro ionol*
2-(1,1-dimethylethyl)cyclohexanol*
3-(1,1-dimethylethyl)cyclohexanol*
4-(1,1-dimethylethyl)cyclohexanol*
4-isopropyl cyclohexanol
6,6-dimethyl-bicyclo[3.3.1]hept-2-ene-2-ethanol
6,6-dimethyl-bicyclo[3.1.1]hept-2-ene-methanol*
p-menth-8-en-3-ol*
3,3,5-trimethyl cyclohexanol
2,4,6-trimethyl-3-cyclohexenyl-methanol*
4-(1-methylethyl)cyclohexyl-methanol*
4-(1,1-dimethylethyl)cyclohexanol
2-(1,1-dimethylethyl)cyclohexanol
2,2,6-trimethyl-alpha-propyl cyclohexane propanol*
5-(2,2,3-trimethyl-3-cyclopentenyl)-3-methylpentan-2-ol*
3-methyl-5-(2,2,3-trimethylcyclopent-3-enyl)pent-4-en-2-ol*
2-ethyl-4(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol*
4-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)-cyclohexanol*
2-(2-methylpropyl)-4-hydroxy-4-methyl-tetrahydropyran*
2-cyclohexyl propanol*
2-(1,1-dimethylethyl)-4-methyl cyclohexanol*
1-(2-tert-butyl-cyclohexyloxy)-2-butanol*
1-(4-isopropyl-cyclohexyl)-ethanol*
2,6-dimethyl-oct-7-en-2-ol**
2,6-dimethyl-heptan-2-ol**
3,7-dimethyl-octa-1,6-dien-3-ol**
whereby * indicates the preferred organoleptic alcohols and phenols and ** indicate the more preferred organoleptic alcohols and phenols.
Examples of preferred non-organoleptic alcohols and phenols constituting the residue R- in the compounds of formula I are:
serine
tyrosine
threonine
7-hydroxy-4-methyl coumarin
benzyldimethyl-2-hydroxyethylammonium chloride
[polyoxyethylene (4) lauryl ether]
[polyoxyethylene (2) cetyl ether]
[polyoxyethylene (2) stearyl ether]
Other preferred non-organoleptic alcohols and phenols are those with an affinity to fibers or those used in cosmetics and laundry formulations. A list of suitable cosmetic alcohols and phenols can be found in the Cosmetic Ingredient Handbook edited by Joanne M. Nikitakis. Suitable surfactant alcohols can be found e.g. in Surfactants Europe edited by Gordon L. Hollis. Examples of alcohols and phenols with special affinity to fibers are those that contain one or more quaternary amine groups or silicon atoms.
Examples of polyalcohols constituting the residue R- in the compounds of formula I are: diols such as: diethylene glycol, propylene glycol, triethylene glycol, 4,4xe2x80x2-bicyclohexyldiol, N,Nxe2x80x2-bis-(2-hydroxyethyl)ethylenediamine, 1,3-bis-(4-hydroxybutyl)-1,1,3,3-tetramethyl-disiloxane, 1,4-bis-(hydroxymethyl)-cyclohexane triols such as: glycerol, cis,cis-1,3,5-cyclohexanetriol, triethanolamine sugars such as: furanoside and pyranoside sugars such as glucose, fructose polymers such as: hydroxyethylcellulose, hydroxypropylcellulose.
It is a matter of course, that it is not possible to give a complete list of the organoleptic and/or antimicrobial ketones, lactones, alcohols and phenols and non-organoleptic, especially nonfragrant alcohols, phenols and polymeric alcohols which are generated as a result of the desired cleavage of the beta-keto esters of formula I by skin bacteria, by enzymes, by elevated temperatures or by acidic and/or alkaline pH-values. The skilled person is, however, quite aware of those ketones, lactones, alcohols and phenols which provide the desired organoleptic, e.g. fragrance, flavour and odour masking and/or antimicrobial effects.
The compounds of formula I may preferably be used as sustained release odorants and flavours but also to mask or attenuate undesirable odours or to provide additional odours not initially present in consumer products, i.e. personal care products such as cosmetic products destined for application to human skin such as underarm deodorants or antiperspirants or other deodorants contacting the body, or in hand lotions, hair care products such as shampoos and conditioners, baby powders, baby lotions, ointments, foot products, facial cleansers, body wipes, facial makeup, colognes, after-shave lotions, shaving creams, etc. Additional applications include laundry detergents, fabric softeners, fabric softener sheets, (automatic) dishwasher detergents and all purpose cleaners. Further applications are air fresheners and odorants, odour masking agents and/or antimicrobial agents.
The compounds I are also useful in the flavouring and aromatizing of cooked foods. Addition of the beta-keto esters either singly or as a mixture to a cake batter, e.g. a microwave cake batter, serves to impart appropriate baking aromas to the cake as it is heated in the microwave as well as impart flavouring in the finished product. Compounds I are also useful in the flavouring and aromatizing of beverages, e.g. hot beverages such as teas and instant beverages prepared by adding hot water to a powder. Compounds I can also act as slow release agents in acidic or alkaline beverages. Further, these compounds are also useful for flavouring and aromatizing tobacco products, e.g. cigarettes.
The amount required to produce the desired, overall effect varies depending upon the particular compounds of formula I chosen, the product in which it will be used, and the particular effect desired.
For example, depending upon the selection and concentration of the compound chosen, when a compound of the formula I is added either singly or as a mixture, e.g. to a deodorant or laundry product composition at levels ranging from about 0.1 to about 10% by weight, or most preferred about 0.25 to about 4% by weight, an odorant, i.e. at least one odoriferous ketone, lactone, alcohol or phenol in an xe2x80x9corganoleptically effective amountxe2x80x9d is released when the product is used. This newly formed odorant serves to enhance the odour of the product itself or of a fragrance present in the product.
Depending upon the selection and concentration, addition of the compounds I, either singly or as a mixture, to cigarette tobacco at levels ranging from about 5 ppm to about 50,000 ppm tends to enhance the smoking flavour and/or mask undesirable smoking odours. An important property of these compounds I is that the flavourant or odorant is covalently bound as a non-volatile compound and the flavourant or odorant is released only when the tobacco product is ignited and bums.
Addition of the compounds of formula I either separately or as a mixture at levels suitably ranging from about 5 ppm to about 50,000 ppm by weight onto the media enclosing the tobacco serves to incorporate the odorant/flavourant in the side-stream smoke of the tobacco. Air borne flavourants and/or odorants are thus introduced. This newly formed odorant or flavourant serves to enhance or mask the smoking odours depending upon selection and use levels of the compounds I.
As is evident from the above compilation of ketones, lactones, alcohols and phenols, a broad range of known odorants or flavours or mixtures can be generated from precursors of the invention. While manufacturing compositions the precursors of the invention may be used according to methods known to the perfumer, such as e.g. from W. A. Poucher, Perfumes, Cosmetics, Soaps, 2, 7th Edition, Chapman and Hall, London 1974.
The compounds of formula I can be prepared by using standard methods known to the skilled chemist. A wide variety of methods for their preparation is known. One example for this knowledge is Chem.Rev. (1995), 1065-1114.